The role of microglia/macropahages in the amyloid pathology of Alzheimer's Disease (AD) is an area of intense investigation. While inflammation associated with the amyloid deposits in AD brain may contribute to the pathogenesis of the disease (H. Akiyama et al., 2000), macrophages in vitro avidly digest amyloid fibrils (D. M. Paresce et al., 1996; S. D. Webster et al., 2000). A number of recent studies present evidence that grafted monocytes home to plaques in mouse models of amyloid deposition (T. M. Malm et al., 2005; A. K. Stalder et al., 2005) and can restrict amyloid deposition, most probably by phagocytosis and digestion of amyloid fibrils (A. R. Simard et al., 2006; J. El Khoury et al., 2007; K. Takata et al., 2007; T. Town et al., 2008).
However, it has been argued that studies labeling CNS infiltrating monocytes with bone marrow grafts may be confounded by CNS damage produced by the irradiation used to deplete the recipients bone marrow (R. Ladeby et al., 2005; B. Ajami et al., 2007; A. Mildner et al., 2007). This method of labeling circulating monocytes with grafted donor bone marrow may, thus, exaggerate the true extent of monocyte infiltration.
A separate issue is the challenging problem of exploiting gene therapy to treat neurodegenerative disorders such as Alzheimer's disease. Even using advanced methods such as convection enhanced delivery, it is rare that a gene therapy vector can transfect the entire cerebral cortex of a mouse, a region 1/3000th the size of the human cortex (C. Burger et al., 2005; M. T. Krauze et al., 2005; C. N. Cearley and J. H. Wolfe, 2006; N. C. Carty et al., 2008). For almost a decade, the potential use of circulating monocytes which home to sites of CNS pathology has been proposed to overcome this gene delivery problem (F. Imai et al., 1999). However, to date the utility of this approach has not been demonstrated.
A major limitation to gene therapy for brain disorders involves the restricted distribution of gene delivery vectors following intracranial administration In addition, a central question in neuroimmunology concerns the extent to which blood borne monocytes migrate to the CNS in degenerative disorders. Therefore, what is needed is a method whereby circulating monocytes home to amyloid plaques in the brain and can be used as effective gene therapy vectors.